A variety of forms of arthritis show a familial aggregation and, in some types, definite patterns of inheritance. Although these types of arthritis include some of the most prevalent causes of disability, only in recent years has a start been made in the identification of the specific genetic and biochemical abnormalities of metabolism responsible, and in the elucidation of the detailed mechanism by which they lead to arthritis. Even in gouty arthritis where the general pathogenetic mechanism is best understood, only a few of the many underlying genetic factors have so far been characterized, and those only recently. In ochronotic arthritis where the primary genetic and enzyme defect producing alcaptonuria has been well defined, the detailed molecular mechanism by which the accumulating homogentisic acid produces the clinical symptoms of ochronotic arthritis in adult life remains obscure. The primary metabolic defect leading to an increased concentration of inorganic pyrophosphate in synovial fluid of patients with chondrocalcinosis and the precise sequence of events leading to formation of the calcium pyrophosphate crystals responsible for the joint symptoms is not well understood. Specific objectives of the proposed research will be to indentify additional genetic and biochemical factors underlying the various types of heritable arthritis, to determine the mechanism by which the biochemical lesion leads to the pathological process and to devise more rational forms of therapeutic intervention by nutritional or pharmacological agents to prevent the pathology. Studies will first be made in vitro at the molecular, biochemical and cellular level using fibroblasts and permanent lymphoblast lines, as well as cultured chondrocytes from affected patients. Investigations that appear promising in vitro will then be extended to clinicial studies of patients with the various diseases to find evidence of the operation in vivo of the same pathological process identified in vitro. The effectiveness of various avenues of therapeutic intervention in preventing development of the disease will also be evaluated in cells cultured in vitro and in patients in vivo.